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Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that environmental and lifestyle-related factors, such as exercise, nutrition, education, and exposure to (early-life) stress modify the onset, incidence, and progression of AD. Here, we discuss recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing AD. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles, and neuroinflammation. We discuss the idea that stress exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of, for example, amyloid-β accumulation, thereby accelerating cognitive decline and progression of Alzheimer-related changes in model systems of the disease. A better understanding of whether experiences early in life also modify trajectories of cognitive decline and pathology in AD and how the substrates discussed translate to humans may help develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life and increase resilience to developing dementia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: As low titer group O whole blood (LTOWB) increases in popularity, blood centers are finding innovative ways of maintaining the supply. One potential way is collecting LTOWB from parous female donors without testing for HLA antibodies. This in silico simulation predicted the risk of an LTOWB unit containing an HLA antibody and the subsequent risk for an HLA-incompatible transfusion., Methods: An LTOWB blood bank with 1 million units was simulated consisting of male, nulliparous, and parous female donors. The proportion of each donor type was modeled after the sex distribution at US blood centers. The parity of female donors was calculated based on the average number of live births per female depending on her age. HLA-alloimmunization risk was determined by her parity status. The HLA haplotypes of the simulated recipients were derived from the 100 most common HLA haplotypes in the US National Marrow Registry Program database. The proportion of different race/ethnic groups in the US was used to simulate 100,000 LTOWB recipients to whom between 1 and 10 units were administered., Results: Overall, the risk of an LTOWB unit containing at least one HLA antibody was 12.2% and the rate of receiving an HLA-incompatible unit was 21.3%. The risk of receiving an HLA-incompatible unit rose from 4.8% after receipt of one unit to 36.5% after 10 units., Conclusion: Blood collectors and hospitals should evaluate the potential TRALI risk against the benefit of a potentially expanded inventory of LTOWB before collecting plasma-containing products from non-HLA-tested parous female donors., (© 2025 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Introduction: The rate of D-alloimmunization amongst RhD-negative recipients of RhD-positive red blood cell (RBC) transfusions is not certain. Recipients with a short duration between the index RhD-positive transfusion and the last antibody detection test that did not show anti-D might become D-alloimmunized in the future. A regression model was developed to predict how often such patients might develop D-alloimmunization in the future to help account for the immunohematological uncertainty that accompanies having short serological follow up periods., Methods: Using the published literature on recipients who were intentionally transfused with RhD-positive RBCs and serially followed with antibody screens, as well as unpublished datasets, a regression model was constructed to demonstrate the timing of D-alloimmunization for recipients who became D-alloimmunized within 6 months following the index transfusion. The model was then applied to a series of RhD-negative hospitalized recipients of at least one unit of RhD-positive RBCs who did not become D-alloimmunized but who had fewer than 6 months of serological follow up to weight their contribution to the D-alloimmunization rate., Results: Overall, the rate of D-alloimmunization was 21/105 (20.0%). There were 39 patients whose last documented antibody screen was performed between 14 days and 6 months after the index RhD-positive transfusion, and these patients were entered into the weighted model. After applying the model, the D-alloimmunization rate rose to 26.3%., Conclusion: Using a weighted model can help reduce the immunohematological uncertainty that accompanies the inclusion of patients with relatively short serological follow up in studies of RBC alloimmunization., (© 2025 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Introduction: Hemorrhage is a leading cause of death in pediatric patients. Accumulating data suggest that low-titer group O whole blood (LTOWB) improves clinical outcomes in the pediatric population. We examined what ratio of LTOWB to total blood product conferred a survival benefit in transfused pediatric trauma patients., Methods: We retrospectively examined a cohort of injured subjects younger than 18 years from the Trauma Quality Improvement Program database who received any quantity of LTOWB and no documented prehospital cardiac arrest. We created a variable representing the volume of transfused LTOWB divided by the total volume of all transfused blood products administered within the first 4 hours of admission, that is, the proportion of LTOWB transfused. We analyzed increasing proportions of transfused LTOWB to determine whether there was an inflection point conferring increased survival., Results: From 2020 to 2022, 1,122 subjects were included in the analysis. The median (interquartile range) age was 16 (14-17) years. Firearms were the most common mechanism at 47% followed by collisions at 44%. The median composite injury severity score was 25 (16-34). Survival was 91% at 6 hours, 89% at 12 hours, and 88% at 24 hours. We noted an inflection point with improved survival at an LTOWB proportion of ≥30% of total volume of blood products received. The odds of survival at 6, 12, and 24 hours for those receiving ≥30% LTOWB was 1.85 (1.02-3.38), 2.09 (1.20-3.36), and 1.80 (1.06-3.08), and 3.55 (1.66-7.58), 3.71 (1.89-7.27), and 2.69 (1.44-5.02) when excluding those who died within 1 hour, respectively., Conclusion: Among LTOWB recipients, we found that a strategy of using LTOWB comprising at least 30% of the total transfusion volume within the first 4 hours was associated with improved survival at 6, 12, and 24 hours., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2025 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: The development of the breast for lactation occurs throughout pregnancy. It is unknown whether pregnancy complications resulting in poor fetal growth can affect breastfeeding (BF) success., Objectives: We examined whether fetal growth-related pregnancy complications were associated with earlier BF cessation and changes in the concentrations of human milk biomarkers of low milk production., Methods: We used data from the Growing Up in Singapore Toward healthy Outcomes study (n = 954). Human milk concentrations of protein, lactose, citrate, sodium, potassium, and zinc at 3 wk postpartum were available for 180 mother-infant dyads. We examined the associations of fetal growth measures, including term infants born small-for-gestational-age (SGA) (<10th percentile), pregnancies complicated by fetal growth deceleration (second to third trimester fetal growth dropped between major centiles), elevated umbilical artery resistance (>90th percentile) or hypertensive disorders of pregnancy (HDP) with 1) risk of ceasing BF (Cox regression) and 2) concentrations of human milk components (weighted linear regression)., Results: Adjusting for maternal education, smoking exposure, BF intentions, and prepregnancy BMI (in kg/m 2 ), individuals who delivered SGA infants and those with HDP were more likely to breastfeed for a shorter duration when compared to those with uncomplicated pregnancies {adjusted hazard ratio [95% confidence interval (CI)]: 1.45 (1.11, 1.89) and 1.61 (1.14, 2.29), respectively}; associations were nonsignificant for fetal growth deceleration and umbilical artery resistance. SGA was not associated with concentrations of human milk biomarkers, but compared to participants with uncomplicated pregnancies, milk produced by those with HDP contained lower zinc concentrations [adjusted β coefficient (95% CI): -0.56 mg/L (-1.08, -0.04) mg/L]., Conclusions: Individuals with HDP and those with SGA infants tend to breastfeed for a shorter duration; however, only HDP appear to be associated with biomarkers of compromised milk production. Further research and support are needed to help individuals with HDP and SGA achieve their BF goals. This trial was registered at clinicaltrials.gov as NCT01174875., Competing Interests: Conflict of interest KMG, S-YC, and Y-SC are part of an academic consortium that has received research funding from Nestec Société Anonyme (SA). C-TL and DTG receive salaries from an unrestricted research grant from Medela Aktiengesellschaft (AG) administered by The University of Western Australia. All other authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: Serum factors binding to cell nuclei were first described in the 1940s and the antibodies responsible for the binding to self (autoantibodies) discovered in the late 1950s. Routine standardized testing using a cell line (HEp-2) started in the 1980s and continues to evolve., Methods: In addition to the classic immunofluorescence assay (IFA), various immunochemical techniques have been developed for the measurement of antinuclear antibodies (ANAs). The complexity of ANA IFA pattern reading and the varying sensitivities, specificities, and overall clinical performance of the alternative methods often generated controversies and sometimes even confusion among healthcare providers and laboratorians. A better understanding of the historical roots of ANA testing can aid in understanding these controversies and assist with selecting the best performing methods. In this review, we present historic and contemporary ANA testing methods, highlighting the pros and cons of each. We also overview the current practice of ANA testing based on several recent large laboratory surveys., Conclusion: Optimal patient care critically requires that clinicians and laboratorians using ANA testing understand the performance and limitations of the methods used by their institutions, as well as the meaning of the test results. Recently published surveys and standardization efforts initiated by several stakeholder scientific organizations will likely lead to new ANA diagnostic guidelines, to be followed by an improvement in testing practices, management, and outcomes for patients with autoimmune disorders.

Tree-planting is increasingly presented as a cost-effective strategy to maximise ecosystem carbon (C) storage and thus mitigate climate change. Its success largely depends on the associated response of soil C stocks, where most terrestrial C is stored. Yet, we lack a precise understanding of how soil C stocks develop following tree planting, and particularly how it affects the form in which soil C is stored and its associated stability and resistance to climate change. Here, we present changes in C and nitrogen (N) stored as mineral-associated organic matter (OM), occluded particulate OM, free particulate OM and dissolved OM, from four regional chronosequences of Scots pine (Pinus sylvestris L.) forests planted on former grasslands across Scotland. We found that c. 58-68 years after the plantation, bulk soil C and N stocks in the organic layer and the top 20 cm of mineral soil decreased by half relative to unforested grasslands - a decrease roughly equivalent to a third of the simultaneous C gain in the tree biomass. This pattern was driven predominantly by a decrease in the amount of C and N stored as mineral-associated OM, an OM fraction considered as relatively long-lived. Our findings demonstrate the need to estimate C storage in response to tree planting based both on soil C stocks and tree biomass, as the use of the latter alone may significantly over-estimate net C benefits of tree planting on permanent grasslands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction/aim: Patients with myotonic dystrophy type1 (DM1) have reduced lifespan. This study aimed to quantify mortality risks, and evaluate causes and time trends in DM1., Methods: We identified 1021 DM1 patients and 15,104 matched DM1-free controls from the United Kingdom (UK) Clinical Practice Research Datalink. We used Cox proportional hazards regression models to assess differences in all-cause or cause-specific mortality between DM1 patients and matched controls, and computed standardized mortality ratios (SMRs) for comparisons of DM1 patients with the UK general population., Results: DM1 patients were at higher risk of death compared with matched DM1-free controls (hazard ratio [HR] = 2.9, 95% confidence interval [CI] = 2.5-3.4) or the general UK population (SMR = 8.1, 95% CI = 7.3-9.1). The excess risk was primarily attributed to deaths from respiratory failure (HR = 26.7, p < 0.001), aspiration pneumonia (HR = 15.8, p < 0.001), arrythmia, and conduction defects (HR = 15.7, p < 0.001). No mortality risk difference between DM1 patients and matched DM1-free cohort was noted for all cancers combined (p = 0.52). No significant calendar time-related changes in overall survival were seen for DM1 patients (p trend = 0.19). In mortality cause-specific analysis, and compared with patients diagnosed before 1993, death from cancer was on the rise (HR = 2.35, and 5.82 for patients diagnosed 1993-2003, and 2004-2016)., Discussion: Most DM1 patients died of known disease complications. This highlights the need for integrated clinical approaches with more careful and frequent monitoring., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Coronary artery bypass grafting (CABG) has demonstrated long-term mortality benefits in patients with HFREF and obstructive coronary artery disease (CAD), but whether phenotypic heterogeneity influences the benefits of CABG is unknown. We applied clustering analysis to STICHES (Surgical Treatment for Ischemic Heart Failure Extension Study) to identify phenogroups with different long-term risk profiles and investigate differences in CABG benefits between phenogroups., Methods and Results: STICHES was a randomized controlled trial evaluating the effect of CABG in addition to medical therapy versus medical therapy alone. We split the STICHES participants into derivation (n = 753) and validation (n = 459) cohorts. We phenomapped the derivation cohort using penalized model-based clustering. We fit multivariable Cox models to investigate long-term differences in all-cause mortality, cardiovascular (CV) mortality, and a composite of all-cause mortality/CV hospitalization between phenogroups and whether phenogroup assignment modified the effects of CABG on these outcomes. Findings were internally validated on the validation cohort. Four phenogroups were identified in the derivation cohort. The highest-risk group was at a twofold greater risk of death (HR: 2.0, 95% CI: 1.4-2.9, p < 0.001) and CV death (HR: 2.0, 95% CI: 1.3-3.1, p = 0.002), and a 1.5-fold greater risk for death/CV hospitalization (HR: 1.5, 95% CI: 1.1-2.1, p = 0.016). Phenogroup assignment did not modify the effects of CABG on the outcomes (p > 0.05 for all). Similar results were obtained in the validation cohort., Conclusions: The beneficial effects of CABG on all-cause mortality, CV mortality, and a composite of all-cause mortality and CV hospitalization persist despite phenotypic heterogeneity in HFREF and CAD., (© 2025 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n max =39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to further evaluate the evidence for causal relationships of PA with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. Our findings revealed 41 proteins consistently associated with all PA measures and 1,027 proteins associated with at least one PA measure. Both conventional observational and MR study designs converged on proteins that appear to increase as a result of PA, including integrin proteins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, GFRA1, and ADGRG2; and on proteins that appear to decrease as a result of PA such as LEP, LPL, INHBC, CLMP, PTGDS, ADM, OGN, and PI3. Functional enrichment analyses revealed several relevant processes, including cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, several proteins, including GDF15, ITGAV, HPGDS, BCAN, and MENT, were found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis and inflammation, through which PA protects against dementia. Our results provide insights into how PA may affect biological processes and protect from all-cause dementia, and provide avenues for future research into the health-promoting effects of PA.

Haemophilus ducreyi causes the genital ulcer disease chancroid and cutaneous ulcers in children. To study its pathogenesis, we developed a human challenge model in which we infect the skin on the upper arm of human volunteers with H. ducreyi to the pustular stage of disease. The model has been used to define lesional architecture, describe the immune infiltrate into the infected sites using flow cytometry, and explore the molecular basis of the immune response using bulk RNA-seq. Here, we used single cell RNA-seq (scRNA-seq) and spatial transcriptomics to simultaneously characterize multiple cell types within infected human skin and determine the cellular origin of differentially expressed transcripts that we had previously identified by bulk RNA-seq. We obtained paired biopsies of pustules and wounded (mock infected) sites from five volunteers for scRNA-seq. We identified 13 major cell types, including T- and NK-like cells, macrophages, dendritic cells, as well as other cell types typically found in the skin. Immune cell types were enriched in pustules, and some subtypes within the major cell types were exclusive to pustules. Sufficient tissue specimens for spatial transcriptomics were available from four of the volunteers. T- and NK-like cells were highly associated with multiple antigen presentation cell types. In pustules, type I interferon stimulation was high in areas that were high in antigen presentation-especially in macrophages near the abscess-compared to wounds. Together, our data provide a high-resolution view of the cellular immune response to the infection of the skin with a human pathogen.IMPORTANCEA high-resolution view of the immune infiltrate due to infection with an extracellular bacterial pathogen in human skin has not yet been defined. Here, we used the human skin pathogen Haemophilus ducreyi in a human challenge model to identify on a single cell level the types of cells that are present in volunteers who fail to spontaneously clear infection and form pustules. We identified 13 major cell types. Immune cells and immune-activated stromal cells were enriched in pustules compared to wounded (mock infected) sites. Pustules formed despite the expression of multiple pro-inflammatory cytokines, such as IL-1β and type I interferon. Interferon stimulation was most evident in macrophages, which were proximal to the abscess. The pro-inflammatory response within the pustule may be tempered by regulatory T cells and cells that express indoleamine 2,3-dioxygenase, leading to failure of the immune system to clear H. ducreyi .

Introduction: Acute uncomplicated urinary tract infection (UTI) is a common condition with potentially serious sequelae that is mostly diagnosed and managed in primary care settings. Around half of all women have a UTI in their lifetime, and a quarter experience an infection caused by organisms resistant to more than one antibiotic. Reducing inappropriate prescribing of antibiotics is a core tenet of antimicrobial stewardship. However, current diagnostics for UTI are unfit for purpose in acute (highest prescribing) settings, being too slow to inform the required immediate decision-making and often confounded by sample contamination.Rapid point-of-care diagnostic tests (POCTs) that facilitate timely decision-making are potential solutions to this problem. Several such tests have reached advanced stages of technology readiness, but their diagnostic performance has not been evaluated in primary care with clinical users. To progress novel tests towards implementation, a diagnostic field study is required, to allow for parallel and sequential evaluation of multiple tests in a primary care population., Methods and Analysis: We will recruit participants assigned female at birth from primary care clinics in England who contact their clinic with symptoms of acute uncomplicated UTI. Eligible participants will complete a short questionnaire to capture symptoms and symptom severity and will provide a urine sample. Samples will be split and initially tested using novel index tests (POCTs) and conventional urinalysis 'dipstick' at the primary care clinic. The second part of the sample will be processed at a National Health Service-based reference laboratory using a modified reference standard including microscopy, microbiological culture, pathogen speciation and antimicrobial susceptibility testing. The UTI reference standard culture, although based on the national methods, is modified to provide accurate bacterial counts, better to define a microbiological diagnosis of UTI. Susceptibility testing will be performed using 'gold-standard' methods, not usually performed in diagnostic laboratories. The primary outcome will be the diagnostic performance (sensitivity, specificity, positive and negative predictive values) of POCTs for detection of UTI and antimicrobial susceptibility for POCTs that include antimicrobial susceptibility testing. Secondary outcomes will include the symptom profile of patients presenting with uncomplicated UTI, a theoretical determination of how use of POCT results might change prescribing, an understanding of POCT failure rate and qualitative capture of the experiences of those using the POCT to deliver the study in primary care clinics., Ethics and Dissemination: Ethical approval was received from the London Central Research Ethics Committee (23/LO/0371) and the UK Health Research Authority. We will publish the findings of The plaTform fOr Urinary tract infection diagnostiC evAluatioN evaluations in peer-reviewed medical journals and more broadly following a dissemination plan formulated by a communications specialist in consultation with patients and the public., Trial Registration Number: ISRCTN80937472., Competing Interests: Competing interests: It is the intention that technology (POCT), associated consumables and training will be provided free of charge to the study under contractual arrangements that preserve the team’s unrestricted rights to publish results. CCB is a member of the Editorial Advisory Board of BMJ Open., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

As the energy density of lithium-ion batteries (LIBs) increases, the shortened cycle life and the increased safety hazards of LIBs are drawing increasing concerns. To address such challenges, a series of localized high-concentration electrolytes (LHCEs) based on a solvating-solvent mixture of tetramethylene sulfone and trimethyl phosphate and a high flash-point diluent 1H,1H,5H-octafluoropentyl 1,1,2,2-tetrafluoroethyl ether were designed. The LHCEs exhibited nonflammability and greatly suppressed heat release at elevated temperatures, which would potentially improve the safety performance of the LIBs. Moreover, the optimal LHCE achieved capacity retentions of 87.1% and 81.7% in graphite||LiNi 0.8 Mn 0.1 Co 0.1 O 2 cells after 500 cycles at 25 and 45 °C, respectively, which were significantly higher than the conventional electrolyte, whose capacity retentions were only 75.2% and 38.5% under the same conditions. Mechanistic studies revealed that the LHCE not only formed a more robust solid electrolyte interphase but also exhibited improved anodic stability, compared with the conventional electrolyte. This work sheds light on rational electrolyte design for high-energy density LIBs with high battery performance and low safety concerns.

The study of the neural circuitry underlying complex mammalian decision-making, particularly cognitive flexibility, is critical for understanding psychiatric disorders. To test cognitive flexibility, as well as potentially other decision-making paradigms involving multimodal sensory perception, we developed FlexRig, an open-source, modular behavioral platform for use in head-fixed mice. FlexRig enables the administration of tasks relying upon olfactory, somatosensory, and/or auditory cues and employing left and right licking as a behavior readout and reward delivery mechanism. The platform includes hardware and software components that are customizable, scalable, and portable, supporting a variety of behavioral assays. Using FlexRig, we established a head-fixed task to model attentional set-shifting, offering a new tool for neuroscience research that enhances the capacity for investigation of cognitive processes and their neural substrates, with broad applications in translational neuroscience., Competing Interests: The authors declare no competing financial interests., (Copyright © 2025 Cristino et al.)

Introduction: Whole blood resuscitation is associated with survival benefits in observational cohort studies. The mechanisms responsible for outcome benefits have not been adequately determined. We sought to characterize the achievement of hemostasis across patients receiving early whole blood versus component resuscitation. We hypothesized that achieving hemostasis would be associated with outcome benefits and patients receiving whole blood would be more likely to achieve hemostasis., Methods: We performed a post hoc retrospective secondary analysis of data from a recent prospective observational cohort study comparing early whole blood and component resuscitation in patients at risk of hemorrhagic shock. Achievement of hemostasis was defined by receiving a single unit of blood or less, including whole blood or red cells, in any 60-minute period, over the first 4 hours from the time of arrival. Time-to-event analysis with log-rank comparison and regression modeling were used to determine the independent benefits of achieving hemostasis and whether achieving hemostasis was associated with whole blood resuscitation., Results: For the current analysis, 1,047 patients met the inclusion criteria for the study. When we compared patients who achieved hemostasis versus those who did not, achievement of hemostasis had significantly more hemostatic coagulation parameters, had lower transfusion requirements, and was independently associated with 4-hour, 24-hour and 28-day survival. Whole blood patients were significantly more likely to achieve hemostasis (88.9% vs. 81.1%, p < 0.001). Whole blood patients achieved hemostasis earlier (log-rank χ2 = 8.2, p < 0.01) and were independently associated with over twofold greater odds of achieving hemostasis (odds ratio, 2.4; 95% confidence interval, 1.6-3.7; p < 0.001)., Conclusion: Achievement of hemostasis is associated with significant outcome benefits. Early whole blood resuscitation is associated with a greater independent odds of achieving hemostasis and at an earlier time point. Reaching a nadir transfusion rate early following injury represents a possible mechanism of whole blood resuscitation and its attributable outcome benefits., Level of Evidence: Secondary Analysis; Level III., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Background: Whether a detected virus or bacteria is a pathogen that may require treatment, or is merely a commensal 'passenger', remains confusing for many infections. This confusion is likely to increase with the wider use of multi-pathogen PCR., Objectives: To propose a new statistical procedure to analyse and present data from case-control studies clarifying the probability of causality., Methods: We conducted a case-control study in US outpatient settings that enrolled patients aged 18 to 75 years with acute lower respiratory tract infection and controls without respiratory symptoms. Patients underwent multi-pathogen PCR testing. The positive etiologic predictive value was calculated to estimate the probability that each potential pathogen was the cause of symptoms. The outcome was illustrated using a modified forest plot and by classifying pathogens into five categories clarifying the probability for causality., Results: We enrolled 618 adult cases and 497 asymptomatic controls. The modified forest plot and the classification of risk for causality aimed to facilitate understanding. Pathogens likely to be causative when present included influenza A and B, SARS-CoV-2, rhinovirus, and parainfluenza viruses, while Staphylococcus aureus is almost always commensal. Broad confidence intervals for the positive etiologic predictive value made it difficult to draw conclusions for potential pathogens with low prevalence., Conclusion: This pilot study shows that the proposed statistical approach is likely to be practical for analysing larger case-control studies or for a meta-analysis of multiple studies. This method may help when interpreting the results from multi-pathogen PCR.

Background: Investigators and funding organizations desire knowledge on topics and trends in publicly funded research but current efforts for manual categorization have been limited in breadth and depth of understanding., Purpose: We present a semi-automated analysis of 21 years of R-type National Cancer Institute (NCI) grants to departments of radiation oncology and radiology using natural language processing (NLP)., Methods: We selected all non-education R-type NCI grants from 2000 to 2020 awarded to departments of radiation oncology/radiology with affiliated schools of medicine. We used pre-trained word embedding vectors to represent each grant abstract. A sequential clustering algorithm assigned each grant to one of 60 clusters representing research topics; we repeated the same workflow for 15 clusters for comparison. Each cluster was then manually named using the top words and closest documents to each cluster centroid. The interpretability of document embeddings was evaluated by projecting them onto 2 dimensions. Changes in clusters over time were used to examine temporal funding trends., Results: We included 5,874 grants totaling 1.9 billion dollars of NCI funding over 21 years. The human-model agreement was similar to the human interrater agreement. Two-dimensional projections of grant clusters showed two dominant axes: physics-biology and therapeutic-diagnostic. Therapeutic and physics clusters have grown faster over time than diagnostic and biology clusters. The three topics with largest funding increase were Imaging biomarkers, Informatics, and Radiopharmaceuticals, which all had a mean annual growth of >$218,000. The three topics with largest funding decrease were Cellular stress response, Advanced imaging hardware technology, and Improving performance of breast cancer computer-aided detection (CAD), which all had a mean decrease of >$110,000., Conclusion: We developed a semi-automated NLP approach to analyze research topics and funding trends. We applied this approach to NCI funding in the radiological sciences to extract both domains of research being funded and temporal trends., Competing Interests: Declaration of competing interest None, (Copyright © 2025. Published by Elsevier Inc.)

Data regarding cardiogenic shock (CS) from safety-net hospitals serving socioeconomically-disadvantaged patients are limited. In addition, little is known regarding long-term outcomes and management of heart failure-related CS (HF-CS), a population potentially especially vulnerable to adverse social determinants of health (SDOH). A single-center retrospective cohort study of patients with Stage C, D, or E CS at a public safety-net hospital between 2017 and 2023 was performed. Management and outcomes were compared between patients with HF-CS and myocardial infarction-CS (AMI-CS). The primary outcome was survival through 2 years. The cohort included 378 patients (median age 57y, 44% Black race, 35% Hispanic ethnicity, 81% HF-CS, 19% AMI-CS); 23% received mechanical circulatory support. Thirty-day mortality was lower among patients with HF-CS than AMI-CS (16% vs 28%; HR 0.50 [95% CI 0.30 to 0.84], p = 0.01]). In contrast, mortality from 31 days through 2 years was higher after HF-CS (45% vs 22%, HR 1.94 [1.11 to 3.38], p = 0.02). At long-term follow-up, 53% of survivors were on beta blockers and 32% on no guideline-directed medical therapies. Eighteen patients (5%) received transplant or left ventricular assist device, all of whom had HF-CS and survived through available follow up (median 2.3y [0.9 to 4.0]). In conclusion, in a large safety-net hospital serving a diverse population with adverse SDOH, HF-CS was much more common than AMI-CS, with lower short-term but higher long-term mortality in HF-CS. Use of advanced therapies was low, with favorable survival among patients who received these. These results highlight the importance of expanding access to specialized heart failure care for socially vulnerable patients with CS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Objective: To determine the feasibility, efficacy, and safety of cold stored compared to room temperature platelet transfusion in patients with traumatic brain injury., Summary Background Data: Data demonstrating the safety and efficacy of cold stored platelet transfusion are lacking following traumatic brain injury., Methods: A phase 2, randomized, open label, clinical trial was performed at a single U.S. trauma center. Traumatic brain injured patients with positive brain imaging and a need for platelet transfusion received up to two apheresis units of cold stored platelets stored out to 14 days versus standard care room temperature platelet transfusion. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was the 6-month Glasgow Coma Scale-Extended score., Results: The 6-month Glasgow Outcome Scale-Extended score distributions were not different across cold stored and room temperature platelet arms (OR-1.58, 95%CI 0.71 to 3.54, P=0.27). A lower rate of neurosurgical craniotomy/craniectomy was found for those receiving cold stored platelets (difference -14.4%, 95%CI -26.5% to -2.3%, P=0.03). Adverse event rates did not differ across groups. The storage age of the cold stored product was not associated with outcome differences., Conclusions and Relevance: In brain injured patients requiring platelet transfusion, early cold stored platelet transfusion is feasible, and did not result in improved 6-month Glasgow Coma Scale-Extended scores. Early cold stored platelet transfusion was associated with a lower rate of neurosurgical operative intervention without an increase in adverse events. The storage age of the cold stored platelet product was not associated with outcome differences. Future phase 3 clinical trials are required to determine clinical outcome differences and safety attributable to cold stored platelet transfusion following traumatic brain injury., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Bipolar disorder is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown 2 . We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings 3 , and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder 4 , highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder., Competing Interests: Competing interests: T.E.T., H. Stefansson and K.S. are employed by deCODE Genetics/Amgen. E.A.S. is an employee of Regeneron Genetics Center and owns stocks of Regeneron Pharmaceutical. K.-H.L. and X.W. are employed by 23andMe. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and served on advisory boards relating to drugs used in affective and related disorders for several companies (AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allergan, Bionomics and Sumitomo Dainippon Pharma), was Lead Investigator for the Embolden study (AstraZeneca), BCI Neuroplasticity study and Aripiprazole Mania study, and is an investigator for Janssen, Lundbeck, Livanova and Compass. J.I.N. is an investigator for Janssen. P.F.S. is on the advisory committee and a shareholder of Neumora Therapeutics. G.B. reports consultancy and speaker fees from Eli Lilly and Illumina, and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A.A. has served as a speaker for Janssen, Lundbeck and Sunovion, and as a consultant for Cortechs.ai. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity and the Mohn Medical Imaging and Visualization Center; and has received research funding from General Electric Healthcare. E.V. has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. S.K.-S. received author’s, speaker’s and consultant honoraria from Janssen, Medice Arzneimittel Pütter GmbH and Takeda outside of the current work. A. Serretti is or has been a consultant and/or speaker for: Abbott, AbbVie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. J.R.D. has served as an unpaid consultant to Myriad-Neuroscience (formerly Assurex Health) in 2017 and 2019, and owns stock in CVS Health. B.M.N. is a member of the scientific advisory board at Deep Genomics, and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. B.-C.L., J.-W.K., Y.K.L., J.H.K., M. J. Cheon and D.J.K. are employed by Genoplan. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. I.B.H. is also the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M (AUD) Australian Government-funded Project Synergy (2017–2020; a 3-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. M.J.O. and M.C.O. have received funding from Takeda Pharmaceuticals and Akrivia Health outside the scope of the current work. P. B. Mitchell. has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the past 3 years; has also received travel awards (airplane tickets and hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial and Medice; and the Department of Psychiatry chaired by J.A.R.-Q. received unrestricted educational and research support from the following companies in the past 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubió. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Rod and cone photoreceptor cells are specialized neurons responsible for transforming the information reaching the eyes in the form of photons into the language of neuronal activity. Rods are the most prevalent photoreceptor type, primarily responsible for light detection under conditions of limited illumination. Here we demonstrate that human rods have a morphological organization unique among all described species, whereby the cell soma extends alongside the light-sensitive outer segment compartment to form a structure we have termed the "accessory inner segment." These structures have two striking features: they are reinforced by a massive microtubular cytoskeleton and contain electron-dense adhesions that mediate their attachment to outer segments. Given that the spacing of human rod photoreceptors is sparser than in most other species, the accessory inner segment likely provides mechanical support to the closely apposed outer segment. This discovery expands our understanding of the human retina and directs future studies of human photoreceptor function in health and disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms., Competing Interests: Declaration of interests The authors have declared no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Right heart catheterization (RHC) provides critical hemodynamic insights by measuring atrial, ventricular, and pulmonary artery pressures, as well as cardiac output (CO). Although the use of RHC has decreased, its application has been linked to improved outcomes. Advanced hemodynamic markers such as cardiac power output (CPO), aortic pulsatility index (API), pulmonary artery pulsatility index (PAPi), right atrial pressure to pulmonary capillary wedge pressure ratio (RAP/PCWP) and right ventricular stroke work index (RVSWI) have been introduced to enhance risk stratification in cardiogenic shock (CS) and end-stage heart failure (HF) patients. CPO has emerged as a potent prognostic tool, with values below 0.6 Watts significantly associated with mortality. Similarly, API and PAPi have demonstrated strong predictive power for adverse outcomes, including death and the need for advanced HF therapies. RAP/PCWP ratio is shown to be a valuable a prognostic tool for RV dysfunction, mortality, and adverse outcomes. Despite mixed evidence on the prognostic utility of RVSWI, its physiologic relevance in assessing right ventricular function remains important. A novel clinical observation, involving patients with an RAP numerically greater than pulmonary artery saturation, was associated with a 71% 30-day mortality rate, underscoring the potential prognostic value of this finding. This review aims to summarize key advanced hemodynamic markers and their role in improving risk stratification and guiding treatment in CS and end-stage HF. The integration of these markers into clinical practice holds the potential to enhance personalized care and improve outcomes for patients with CS and advanced HF., Competing Interests: Declarations. Competing Interests: Sotiria Liori serves as an associate editor of this journal., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cervical cancer disparities persist among minoritized women due to infrequent screening and poor follow-up. Structural and psychosocial barriers to following up with colposcopy are problematic for minoritized women. Evidence-based interventions using patient navigation and tailored telephone counseling, including the Tailored Communication for Cervical Cancer Risk (TC3), have modestly improved colposcopy attendance. However, the efficacious TC3 intervention is human resource-intense and could have greater reach if adapted for mobile health, which increases convenience and access to health information., Objective: This study aimed to describe feedback from clinic staff members involved in colposcopy processes and patients referred for colposcopy regarding adaptions to the TC3 phone-based intervention to text messaging, which addresses barriers among those referred for colposcopy after abnormal screening results., Methods: Semistructured depth qualitative interviews were conducted over Zoom [Zoom Communications, Inc] or telephone with a purposive sample of 22 clinic staff members (including clinicians and support staff members) and 34 patients referred for colposcopy from 3 academic obstetrics and gynecology (OB-GYN) clinics that serve predominantly low-income, minoritized patients in different urban locations in New Jersey and Pennsylvania. Participants were asked about colposcopy attendance barriers and perspectives on a proposed text message intervention to provide tailored education and support in the time between abnormal cervical screening and colposcopy. The analytic team discussed interviews, wrote summaries, and consensus-coded transcripts, analyzing output for emergent findings and crystallizing themes., Results: Clinic staff members and patients had mixed feelings about a text-only intervention. They overwhelmingly perceived a need to provide patients with appointment reminders and information about abnormal cervical screening results and colposcopy purpose and procedure. Both groups also thought messages emphasizing that human papillomavirus is common and cervical cancer can be prevented with follow-up could enhance attendance. However, some had concerns about the privacy of text messages and text fatigue. Both groups thought that talking to clinic staff members was needed in certain instances; they proposed connecting patients experiencing complex psychosocial or structural barriers to staff members for additional information, psychological support, and help with scheduling around work and finding childcare and transportation solutions. They also identified inadequate scheduling and reminder systems as barriers. From this feedback, we revised our text message content and intervention design, adding a health coaching component to support patients with complex barriers and concerns., Conclusions: Clinic staff members and patient perspectives are critical for designing appropriate and relevant interventions. These groups conveyed that text message-only interventions may be useful for patients with lesser barriers who may benefit from reminders, basic educational information, and scheduling support. However, multimodal interventions may be necessary for patients with complex barriers to colposcopy attendance, which we intend to evaluate in a subsequent trial., (©Jennifer R Hemler, Rachel B Wagner, Brittany Sullivan, Myneka Macenat, Erin K Tagai, Jazmarie L Vega, Enrique Hernandez, Suzanne M Miller, Kuang-Yi Wen, Charletta A Ayers, Mark H Einstein, Shawna V Hudson, Racquel E Kohler. Originally published in JMIR Formative Research (https://formative.jmir.org), 14.01.2025.)

Competing Interests: Competing interests statement:The authors declare no competing interest.

Improving the utility of biomedical devices implanted in subcutaneous tissue by modulating the innate immune response common to these implants is of great interest to improve their utility. Uncontrolled, most biomedical devices produce an immune reaction known broadly as the foreign body response (FBR), which ultimately isolates the device from the native tissue. The use of electrospun fibers to create a porous surface that promotes tissue in-growth and regeneration represents a new paradigm in FBR modulation. A vast number of parameters can be adjusted in the electrospinning process to tune the type and quality of the resulting electrospun matrix, which in turn has varying outcomes with respect to the FBR. In this review, the fabrication and utility of electrospun fiber scaffolds for mitigating the FBR are described, with details of how fiber properties and surface modifications alter immune response for specific biomedical applications.

Proton pump inhibitors (PPIs) are one of the standards of care of eosinophilic esophagitis (EoE) treatment, though PPI response rates are variable ranging from 23 to 63% in pediatric studies. We sought to determine if expression of select genes in esophageal mucosa can predict PPI responsiveness in EoE. Children with a new diagnosis of EoE (15 or more eosinophils/hpf on esophageal biopsy) were prospectively treated with 8 weeks of PPI therapy before follow-up esophagogastroduodenoscopy (EGD). Children with <15 eosinophils/hpf on follow-up were classified as having PPI-Responsive EoE (PPI-R) and ≥ 15 eosinophils/hpf as PPI-Nonresponsive EoE (PPI-NR). Using the Nanostring nCounter Analysis System, mRNA expression of a custom panel of genes was measured in esophageal biopsies. Immunohistochemical staining of biopsies was performed. Among children with EoE, 32% (8/25) had PPI-R EoE. ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC and IL13 had higher expression in PPI-NR EoE compared to PPI-R EoE or controls. Immunohistochemical staining of ATP12A was higher among PPI-R EoE and PPI-NR EoE, compared to non-EoE controls. In this study, PPI-NR EoE had significantly higher baseline gene expression of mast cell, cytokine, proton pump, and eosinophil genes compared to PPI-R EoE. PPIs may be involved in an inflammatory cascade of mast cell activation that stimulates IL-13 release, which upregulates ATP12A and ATP4A that leads to eosinophil recruitment. Histologic PPI failure may occur when increased gene expression of these components is high and cannot be overcome pharmacologically, especially in the case of proton pump genes., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Deep learning is a promising approach to increase reproducibility and time-efficiency of gross tumor volume (GTV) delineation in head and neck cancer, but model evaluation primarily relies on manual GTV delineations as reference annotation, which are subjective and tend to overestimate tumor volume. This study aimed to validate a deep learning model for laryngeal and hypopharyngeal GTV segmentation with pathology and to compare its performance with clinicians' manual delineations., Methods and Materials: A retrospective data set of 193 patients with laryngeal and hypopharyngeal cancer was used to train a deep learning model with clinical GTV delineations as reference. For validation, a data set comprising 18 patients who underwent imaging before total laryngectomy was used, with histopathology-based (n = 16) tumor delineations as ground truth. The performance of the automatic segmentations was compared with that of clinicians' manual delineations, both quantitatively and qualitatively., Results: Median sensitivity (0.90 and 0.91) and largest required clinical target volume margin (6.4 and 6.6 mm) were comparable between automatic and manual GTV delineations. The positive predictive value yielded the only significant difference between automatic and manual GTV delineations, with medians of 0.52 and 0.61, respectively (P = .03). Clinical target volumes derived from automatic and manual GTVs exhibited similar sizes (median of 44.5 and 40.1 mL) and achieved a sensitivity of 1.00 in 13/16 and 14/16 tumors, respectively. Automatic segmentations were considered clinically acceptable in 67% of cases, compared with 63% of manual delineations., Conclusions: The proposed deep learning model for laryngeal and hypopharyngeal GTV segmentation achieved comparable results with clinicians' manual delineations, showing the potential for more consistency and efficiency in the radiation therapy workflow., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Amplification of cyclin-dependent kinase 4 (CDK4) and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests that inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-Molecular Analysis for Therapy Choice trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors., Patients and Methods: Patients had a solid malignancy or lymphoma with progression on at least one systemic therapy for advanced disease or with no standard-of-care therapy available. Tumors with ≥7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1 to 21 of a 28-day cycle. The primary endpoint was objective response rate., Results: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for objective response rate endpoint. Among the 25 patients in the primary cohort, one patient had a partial response, 4 patients had stable disease, and 16 patients had progressive disease as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a partial response, 10 patients had stable disease, and 21 patients had progressive disease as best response. Partial response and stable disease were seen only in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months., Conclusions: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, although central nervous system tumors may be worthy of future investigation., (©2024 American Association for Cancer Research.)

Almost all cervical cancers are caused by human papillomaviruses (HPVs). In most cases, HPV DNA is integrated into the human genome. We found that tumor-specific, HPV-human DNA junctions are detectable in serum cell-free DNA of a fraction of cervical cancer patients at the time of initial treatment and/or at six months following treatment. Retrospective analysis revealed these junctions were more frequently detectable in women in whom the cancer later recurred. We also found that cervical cancers caused by HPV types outside of phylogenetic clade α9 had a higher recurrence frequency than those caused by α9 types in both our study and The Cancer Genome Atlas cervical cancer database, despite the higher prevalence of α9 types including HPV16 in cervical cancer. Thus, HPV-human DNA junction detection in serum cell-free DNA and HPV type determination in tumor tissue may help predict recurrence risk. Screening serum cell-free DNA for junctions may also offer an unambiguous, non-invasive means to monitor absence of recurrence following treatment.

Background and Aims: Longitudinal outcomes in children with metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear due to the absence of a standardized monitoring approach. This study aimed to (1) define improvement and worsening in children with MASLD, (2) estimate rates of improvement or deterioration with the standard of care (SOC) over 1 and 2 years, and (3) identify baseline and longitudinal factors associated with improvement or worsening., Approach and Results: Using data from 2 large randomized controlled trials, we derived definitions for composite improvement and worsening of MASLD based on associations between changes in ALT, GGT, and liver histology after 1 and 2 years. Improvement was defined as ≥40% decrease in ALT and ≥20% decrease in GGT and worsening as ≥20% increase in both ALT and GGT. We applied definitions to a cohort of 440 children with MASLD. After 1 year of SOC, 22% of children with MASLD showed improvement, increasing to 31% after 2 years. However, 20% showed worsening after both 1 and 2 years despite receiving SOC. Logistic regression analysis, employing stepwise model selection, identified changes in body mass index z-score and cholesterol to be most associated with improvement or deterioration., Conclusions: This study developed criteria for improvement and worsening in children with MASLD over 1 and 2 years of follow-up. With SOC, over one-quarter of children are likely to improve while one-fifth of children are likely to worsen. Targeting interventions that affect body mass index and lipid parameters may help improve MASLD over time., (Copyright © 2025 American Association for the Study of Liver Diseases.)

Multiferroic materials host both ferroelectricity and magnetism, offering potential for magnetic memory and spin transistor applications. Here, we report a multiferroic chalcogenide semiconductor Cu 1-x Mn 1+y SiTe 3 (0.04 ≤ x ≤ 0.26; 0.03 ≤ y ≤ 0.15), which crystallizes in a polar monoclinic structure ( Pm space group). It exhibits a canted antiferromagnetic state below 35 kelvin, with magnetic hysteresis and remanent magnetization under 15 kelvin. We demonstrate multiferroicity and strong magnetoelectric coupling through magnetodielectric and magnetocurrent measurements. At 10 kelvin, the magnetically induced electric polarization reaches ~0.8 microcoulombs per square centimeter, comparable to the highest value in oxide multiferroics. We also observe possible room-temperature ferroelectricity. Given that multiferroicity is very rare among transition metal chalcogenides, our finding sets up a unique materials platform for designing multiferroic chalcogenides.

Pelvic venous disorders (PeVDs) are rarely considered as a cause of chronic pelvic pain in women being evaluated by nonvascular specialists. A Society of Interventional Radiology (SIR) Foundation-sponsored Research Consensus Panel addressing this issue identified multiple gaps in the literature and made recommendations to enhance the evidence. Since publication of these recommendations in 2019, significant progress has been made in developing the necessary tools to improve the ability to conduct rigorous clinical studies and advance the evidence supporting the diagnosis and treatment of PeVD. This report summarizes the 5-year impact of the panel's recommendations. The investment made by SIR Foundation to host a Research Consensus Panel on PeVD has facilitated enduring academic productivity related to this clinical issue., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Genomic data on Clostridioides difficile from the African continent are currently lacking, resulting in the region being under-represented in global analyses of C. difficile infection (CDI) epidemiology. For the first time in Nigeria, we utilized whole-genome sequencing and phylogenetic tools to compare C. difficile isolates from diarrhoeic human patients ( n =142), livestock ( n =38), poultry manure ( n =5) and dogs ( n =9) in the same geographic area (Makurdi, north-central Nigeria) and relate them to the global C. difficile population. In addition, selected isolates were tested for antimicrobial susceptibility ( n =33) and characterized by PCR ribotyping ( n =53). Hierarchical clustering of core-genome multilocus sequence typing (cgMLST) allelic profiles revealed large diversity at the level HC150 (i.e. clusters of related genomes with maximally 150 pairwise allelic differences), which was previously shown to correlate with PCR ribotypes (RT). While several globally disseminated strains were detected, including HC150&#95;1 (associated with RT078), HC150&#95;3 (RT001) and HC150&#95;3622 (RT014), 42 HC150 clusters (79%) represented unique genotypes that were new to the public genomic record, and 16 (30%) of these were novel PCR ribotypes. Considerable proportions of the C. difficile isolates displayed resistance to fluoroquinolones, macrolides and linezolid, potentially reflecting human and animal antibiotic consumption patterns in the region. Notably, our comparative phylogenomic analyses revealed human-human, human-livestock and farm-farm sharing of near-identical C. difficile genomes (≤2 core-genome allelic differences), suggesting the continued spread of multiple strains across human and animal (pig, poultry, cattle and dog) host populations. Our findings highlight the interconnectivity between livestock production and the epidemiology of human CDI and inform the need for increased CDI awareness among clinicians in this region. A large proportion of C. difficile strains appeared to be unique to the region, reflecting both the significant geographic patterning present in the C. difficile population and a general need for additional pathogen sequencing data from Africa.

Objective: The aim of this study was to understand the relationship between cardiovascular disease (CVD) risk and liver steatosis and fibrosis among people with HIV (PLWH) at least 40 years of age on antiretroviral therapy (ART) in low and middle-income countries (LMIC)., Design: We used cross-sectional behavioral and clinical data collected during study enrollment visits in 2020-2022 for the Sentinel Research Network of International epidemiology Databases to Evaluate AIDS (SRN of IeDEA)., Methods: Ten-year CVD risk was calculated using 2019 WHO nonlaboratory and laboratory models. Transient elastography was used to assess liver disease. Presence of steatosis and significant fibrosis were defined by controlled attenuation parameter (CAP) at least 248 dB/m and liver stiffness measurement (LSM) at least 7.1 kPa, respectively. Participants with viral hepatitis, hazardous alcohol consumption, and unsuppressed HIV viral load were excluded from the analysis. Logistic regression was used to estimate odds ratios, adjusting for study site, CD4 +  T cell count, stavudine and didanosine exposure, and in models stratified by sex and geographic region., Results: There were 1750 participants from nine LMIC. Median CVD risk was 3% for both nonlaboratory and laboratory-based models. Adjusted odds ratios (ORs) for steatosis and significant fibrosis associated with laboratory CVD risk (≥10 vs. <5%) were OR = 1.83 [95% confidence interval (95% CI) = 1.21-2.76; P  = 0.004] and OR = 1.62 (95% CI = 0.85-3.07; P  = 0.14), respectively. Associations of CVD risk with steatosis were stronger in men and among participants at study sites outside Africa., Conclusion: Higher CVD risk was associated with steatosis but not with significant fibrosis in PWH in our LMIC cohort., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cranial vault remodeling (CVR) is a common procedure for correcting sagittal craniosynostosis. Some approaches leave significant craniectomy defects. The authors investigated the reosteogenesis in different cranial defect areas after CVR. A cross-sectional study was conducted in nonsyndromic sagittal craniosynostosis. Available early postoperative computed tomography (CT) scans were analyzed. The segmentation of three-dimensional reconstructed images was performed. Different cranial defect areas, including coronal, vertex, and occipital regions, were further investigated using an automated three-dimensional analysis software for reosteogenesis percentage. Forty-four CT scans were included. The average age at CVR was 8.8 months. The median time of postoperative CT scans was 6.1 weeks. The median bone reformation percentage of the entire cranial defect was 56.7%. Given the similar postoperative CT timing, the median bone reformation at the coronal, vertex, and occipital areas demonstrated 44.21%, 41.13%, and 77.75%, respectively ( P < 0.001). In the simultaneously removed coronal and lambdoid sutures, there were 45% with coronal and lambdoid sutures reformation, followed by lambdoid suture reformation alone, no suture reformation and coronal reformation alone in 35%, 20%, and 0%, respectively ( P = 0.013). There was no coronal reformation in the removed coronal suture group. However, 40% demonstrated lambdoid suture reformation after the isolated lambdoid suture removal. The occipital region has the highest reosteogenesis compared with the other cranial defects after CVR in nonsyndromic sagittal craniosynostosis. Within the removed previous patent sutures, the lambdoid suture reformation showed a higher rate than the coronal suture., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Extensor tendon injuries are commonly encountered after trauma. These injuries often result in acute weakness and have widely differing treatment options depending on the severity and the location of the injury within the upper extremity. Zone I injuries can often be treated nonoperatively with the potential for pinning of any large bony avulsion fragments. For zone II injuries, the tendons are often amenable to surgical repair with extension splinting for 6 weeks. Injuries at the central slip in zone III are often treated with closed extension splinting. In zone IV, these injuries are often treated similarly to those in zone II. Zone IV injuries without any extensor lag can often be treated nonoperatively with splinting; however, extension weakness is an indication for surgical repair. In zone V, the tendon is often substantial enough to hold sutures; however, because these injuries are often a result of a human bite wound, these are susceptible to more delayed repair or reconstruction following irrigation and débridement. Injuries in zone VI are often treated with direct repair as well as immobilization. More proximally, over the level of the wrist joint and up through to the forearm, these injuries are often treated with direct repair.

Competing Interests: Disclosures See Appendix 1 for a comprehensive list of author disclosures.